Improvement of ventilation-induced lung injury in a rodent model by inhibition of inhibitory κB kinase

Shu, Yusheng; Tao, Wei; Miao, Qian-Bing; Zhu, Yabing; Yang, Yi-Feng

doi:10.1097/ta.0000000000000229

Cited by 29 publications

(27 citation statements)

References 38 publications

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“…It is also known that patients ventilated with high tidal volumes are at risk for VALI and a higher mortality rate (12,17). Although it is unclear precisely how mechanical stretch may induce lung injury, mechanisms that promote the release of inflammatory mediators including TNF-α, IL-1β, IL-8 and HMGB 1 been implicated (8,12,18). An administration of drugs with anti-inflammatory features has shown a decrease in VILI (12,19,20).…”

Section: Discussionmentioning

confidence: 99%

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Preconditioning of physiological cyclic stretch inhibits the inflammatory response induced by pathologically mechanical stretch in alveolar epithelial cells

Fang

et al. 2017

Exp Ther Med

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Abstract. The aim of the present study was to investigate the effects of preconditioning of physiological cyclic stretch (CS) on the overexpression of early pro-inflammatory cytokines [including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-8] during the inflammatory response induced by pathologically mechanical stretch in lung epithelial cells, and to determine its molecular mechanism of action. Cells were subjected to 5% CS for various durations (0,15, 30, 60 and 120 min) prior to 6 h treatment with pathological 20% CS. In a separate experiment, cells were preconditioned with physiological 5% CS or incubated with a nuclear factor (NF)-κB inhibitor, pyrroldine dithiocarbamate (PDTC). The expression levels of inflammatory mediators were measured using reverse transcription-quantitative polymerase chain reaction. NF-κB was quantified using western blot analysis. Preconditioning with physiological 5% CS for 30, 60 and 120 min was demonstrated to significantly attenuate the release of pathologically mechanical stretch-induced early pro-inflammatory cytokines (TNF-α, IL-1β and IL-8) in alveolar epithelial cells (P<0.05) and significantly reduce the expression of NF-κB (P<0.05). Peak suppression was observed in cells preconditioned for 60 min. In the second set of experiments, it was demonstrated that mechanical stretch-induced release of TNF-α, IL-1β and IL-8 was significantly inhibited by both PDTC pretreatment and 5% CS pretreatment alone (all P<0.05). Furthermore, significant inhibition was also observed when both 5% CS pretreatment and PDTC pretreatment was used on mechanical stretch-induced cells (P<0.05), which was markedly greater than the inhibition induced by either pretreatment alone. The present findings suggest that preconditioning with physiological 5% CS is able to inhibit the inflammatory response induced by pathologically mechanical stretch in alveolar epithelial cells. These anti-inflammatory effects are induced, at least in part, by suppressing the NF-κB signaling pathway.

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Section: Discussionmentioning

confidence: 99%

“…Nuclear factor (NF)-κB is required for maximal transcription of various cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-8, and IL-1β (6,7). Furthermore, it has been suggested that inhibitors of NF-κB function may be useful as anti-inflammatory agents (8).…”

Section: Introductionmentioning

confidence: 99%

Preconditioning of physiological cyclic stretch inhibits the inflammatory response induced by pathologically mechanical stretch in alveolar epithelial cells

Fang

et al. 2017

Exp Ther Med

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“…However, other studies have shown that Akt negatively regulates p65 transactivation induced by activation of receptors that recognize either extracellular or intracellular bacterial products (53,54). In addition, the activation of Akt by IKK16 has been recently reported in sepsis (12) and lung injury (13). Overall, these data suggest a complex cross-talk between the Akt and NF-κB signaling pathways, which still warrants further investigation.…”

Section: K K I N H I B I T I O N I M P R O V E S O R G a N I N J U mentioning

confidence: 81%

“…To gain a better insight into the potential mechanisms involved in the beneficial effects of IKK16, we investigated the effects of IKK16 on the Akt-survival pathway, which is known to confer tissue protection (12,13). In HS-rats, HS did not significantly affect the degree of phosphorylation of Akt in either kidney or liver compared with sham-operated rats (Figures 8A, B).…”

Section: Effects Of Ikk16 Treatment On Akt Survival Pathwaymentioning

confidence: 99%

“…The inhibition of IKK complex by IKK16 and the consequent prevention of the activation of NF-κB reduce the cardiac dysfunction, liver injury and renal dysfunction caused by sepsis (12) and ventilation-induced lung injury (13). There is indirect evidence that agents that prevent the activation of NF-κB (for example, calpain inhibitor I) are also of benefit in HS (14).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of IκB Kinase Attenuates the Organ Injury and Dysfunction Associated with Hemorrhagic Shock

Chiazza

Johnson

Patel

et al. 2015

Mol Med

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Nuclear factor-kappa B (NF-κB) activation is widely implicated in multiple organ failure (MOF); however, a direct inhibitor of IκB kinase (IKK), which plays a pivotal role in the activation of NF-κB, has not been investigated in shock. Thus, the aim of the present work was to investigate the effects of an IKK inhibitor on the MOF associated with hemorrhagic shock (HS). Therefore, rats were subjected to HS and were resuscitated with the shed blood. Rats were treated with the inhibitor of IKK or vehicle at resuscitation. Four hours later, blood and organs were assessed for organ injury and signaling events involved in the activation of NF-κB. Additionally, survival following serum deprivation was assessed in HK-2 cells treated with the inhibitor of IKK. HS resulted in renal dysfunction, lung, liver and muscular injury, and increases in serum inflammatory cytokines. Kidney and liver tissue from HS rats revealed increases in phosphorylation of IKKαβ and IκBα, nuclear translocation of NF-κB and expression of inducible isoform of nitric oxide synthase (iNOS). IKK16 treatment upon resuscitation attenuated NF-κB activation and activated the Akt survival pathway, leading to a significant attenuation of all of the above parameters. Furthermore, IKK16 exhibited cytoprotective effects in human kidney cells. In conclusion, the inhibitor of IKK complex attenuated the MOF associated with HS. This effect may be due to the inhibition of the NF-κB pathway and activation of the survival kinase Akt. Thus, the inhibition of the IKK complex might be an effective strategy for the prevention of MOF associated with HS.

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Topotecan alleviates ventilator-induced lung injury via NF-κB pathway inhibition

Wan

Zhan

et al. 2018

Cytokine

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Improvement of ventilation-induced lung injury in a rodent model by inhibition of inhibitory κB kinase

Cited by 29 publications

References 38 publications

Preconditioning of physiological cyclic stretch inhibits the inflammatory response induced by pathologically mechanical stretch in alveolar epithelial cells

Preconditioning of physiological cyclic stretch inhibits the inflammatory response induced by pathologically mechanical stretch in alveolar epithelial cells

Inhibition of IκB Kinase Attenuates the Organ Injury and Dysfunction Associated with Hemorrhagic Shock

Topotecan alleviates ventilator-induced lung injury via NF-κB pathway inhibition

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